It has been suggested by many pharmaceutical companies that an oral delivery system is a preferred method of administering therapeutic remedies; it has been estimated that some 85% of all drugs are delivered orally. The ability to deliver a drug orally, allows for increased compliance with the treatment regimen versus an intravenous delivery or even a suppository, which may cause the patient discomfort or subject them to an infection. Other treatments such as inhalation and dermal patches, allow for increased patient compliance versus an intravenous dose, but may require an excess drug product in order to be effective, due to absorption issues and usually requires either expensive equipment or a formulation which is costly to manufacture, test, and administer. Further, oral formulations can be administered without the public noticing while in a public location such as an office or restaurant, where with most other formulations, this may not be the case. The delivery system through which a drug is ingested plays a significant role in the way and the extent to which the compound is absorbed and metabolized. Problems of miscibility and absorption are numerous with such systems. In order to receive the full therapeutic benefit, the drug must be effectively absorbed into the blood stream through the intestine. However, the body possess numerous mechanisms to prevent absorption and expelling a drug back into the intestine before it can reach its site of action. Therein lies the problem, many drug compounds are poorly soluble in an aqueous medium, as found in the stomach, nor will they effectively cross the lumen of the intestine for absorption into the blood stream.
Chief among these mechanisms which prevent absorption through the intestinal wall is that of the p-glycoprotein. The p-glycoprotein is an ATP-powered efflux pump which can transport hundreds of structurally unrelated hydrophobic and amphipathic compounds, including therapeutic drugs, peptides and lipid-like compounds. This polypeptide plays a crucial physiological role in protecting tissues from toxic xenobiotics and endogenous metabolites. This also affects the uptake and distribution of many clinically important drugs. It forms a major component of each of these: the blood-brain barrier, the intestinal lining's defenses against xenobiotics, and the renal tubules mechanisms to accelerate the excretion of many xenobiotics. This transporter restricts the uptake of drugs from the intestine, among other purposes
As a guide for predicting the intestinal absorption of drug substances, the U.S. Food and Drug Administration utilizes the Biopharmaceutical Classification System (BCS) to classify drug substances, including small molecule pharmaceuticals and nutraceuticals compounds, based on both permeability and solubility. BCS Class I drug substances are both highly permeable and highly soluble. BCS Class II drug substances are highly permeable, but have low solubility. BCS Class III drug substances are highly soluble, but have low permeability. BCS Class IV drug substances have both low solubility and low permeability.
There are many BCS Class III and IV drug substances which would be effective therapies for a variety of diseases, but for the fact that they poorly absorb or will not absorb through the intestine.
A first example, include the chemotherapeutic agent, vinblastine, which must delivered intravenously, due to negligible intestinal absorption and its status as a p-glycoprotein substrate. After intravenous injection, vinblastine, is known to cause severe tissue irritation and even damage, which further limits its utility as a chemotherapeutic agent.
A second example involves curcumin, a compound found in turmeric extract, is a known COX-II inhibitor, prophylactic chemotherapeutic agent, histamine release inhibitor and nutritional antioxidant; however, due to p-glycoprotein catalyzed efflux <1%, of an oral dose is absorbed through the intestine. Co-administration of curcumin with the p-glycoprotein inhibitor, piperine, will only increase absorption to approximately 2.4%. The low absorption requires a larger dose of curcumin, in order to reach therapeutic concentrations in the blood stream, which makes it inconvenient for the patient to self-administer and causes an unpalatable after taste, as well as GI discomfort, discoloration of the mouth and feces.
A third example involves cannabidiol (CBD), the non-psychoactive agent found in cannabis species including industrial hemp and marijuana. CBD is also found in flax stalk, and can be legally extracted from this source. CBD is a probable anxiolytic, anticonvulsive, antispasmodic, and antipsychotic drug. It may also be useful in hospital emergency departments to relieve the dysphoric and combative symptoms associated with accidental or deliberate ingestions of some hallucinogenic drugs such as marijuana, synthetic cannabinoids (bath salts), potentially antagonists of NMDA receptors such as dextromethorphan, and agonists of 5HT-2a receptors such as mescaline and lysergic acid diethyl amide (LSD). It is approved in Canada as an anticonvulsive for pediatric use in in the treatment of a severe myoclonic epilepsy of infancy and early childhood, known as Dravet syndrome. However, at only 3% bioavailability, CBD is poorly absorbed through the intestinal lumen, despite having structural characteristics of a prototypical highly absorbent molecule. It is believed that CBD's interaction with the p-glycoprotein efflux transporter is the cause of the poor absorption; thus, by blocking this interaction, it will be possible to increase the bioavailability of a CBD oral dose. CBD is starkly expensive as an oral dosage, and alternative formulations which increase absorption would reduce the cost to patients. CBD can be administered by a nebulizer or can be smoked in order to increase the absorption. However, both of these delivery methods have drawbacks which limit their practical use. Nebulizers are expensive, inconvenient, and cannot be used discretely in public. Smoking is perceived as noxious, damaging to exposed property, socially reprehensible by most, and is invariably detrimental to the health of both the patient and bystanders. This is due to the polycyclic aromatic hydrocarbons such as benzo[a]pyrene that are produced by the burning organic material and is subsequently emitted into the air. It is reasonably presumed, therefore, that an oral dosage with good absorption, would be preferable over these alternatives by most patients.
The instant invention is a novel formulation technology which allows for effective oral absorption of low solubility, low permeability and/or p-glycoprotein efflux transporter substrate drugs and herbal extracts, such as vinblastine, curcumin, and CBD. With this technique, these are absorbed effectively through the intestinal lumen with lowered p-glycoprotein catalyzed efflux while being emulsified to compensate for problems with solubility. This technique concurrently addresses a number of formulation problems in the following manners, while the mechanism also aids absorption: 1) inhibition of intestinal p-glycoprotein, mitigating efflux of substrate drugs from enterocytes back into the intestinal lumen; 2) facilitation of mechanisms of absorption that circumvent the p-glycoprotein's reach; 3) this technique places the drug in a microemulsion on contact with water or intestinal chyme mediated by the amphipathic nature of the carbohydrate used in the formula, which has mutual affinity for the drug and the water; this compensates for poor solubility in water; and additionally 4) the drug may be drawn across membranes with the carbohydrate/alcohol formulation by means of hydrophobic affinity. The instant invention, therefore, satisfies the need for a drug substance formulation method which allows for the preparation of drug substances for oral administration, which would otherwise be ill-suited for oral dosage.